1UTS

Designed HIV-1 TAR Binding Ligand

Summary for 1UTS

• Entry DOI: 10.2210/pdb1uts/pdb
• Related: 1UUD 1UUI
• Descriptor: RNA (5'-(*GP*GP*CP*AP*GP*AP*UP*CP*UP*GP*AP*GP *CP*CP*UP*GP*GP*GP*AP*GP*CP*UP*CP*UP*CP*UP*GP*CP*C) -3'), N-[2-(3-AMINOPROPOXY)-5-(1H-INDOL-5-YL)BENZYL]-N-(2-PIPERAZIN-1-YLETHYL)AMINE (2 entities in total)
• Functional Keywords: hiv-1, tar rna, drug design, antiviral, ligand binding, conformational change
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1)
• Total number of polymer chains: 1
• Total formula weight: 9715.11

Authors

Davis, B.,Murchie, A.I.H.,Aboul-Ela, F.,Karn, J. (deposition date: 2003-12-10, release date: 2004-02-12, Last modification date: 2024-05-15)

Primary citation

Murchie, A.I.,Davis, B.,Isel, C.,Afshar, M.,Drysdale, M.J.,Bower, J.,Potter, A.J.,Starkey, I.D.,Swarbrick, T.M.,Mirza, S.,Prescott, C.D.,Vaglio, P.,Aboul-ela, F.,Karn, J.
Structure-based drug design targeting an inactive RNA conformation: exploiting the flexibility of HIV-1 TAR RNA.
J.Mol.Biol., 336:625-638, 2004

PubMed Abstract: The targeting of RNA for the design of novel anti-viral compounds represents an area of vast potential. We have used NMR and computational methods to model the interaction of a series of synthetic inhibitors of the in vitro RNA binding activities of a peptide derived from the transcriptional activator protein, Tat, from human immunodeficiency virus type 1. Inhibition has been measured through the monitering of fluorescence resonance energy transfer between fluorescently labeled peptide and RNA components. A series of compounds containing a bi-aryl heterocycle as one of the three substituents on a benzylic scaffold, induce a novel, inactive TAR conformation by stacking between base-pairs at the site of a three-base bulge within TAR. The development of this series resulted in an enhancement in potency (with Ki < 100 nM in an in vitro assay) and the removal of problematic guanidinium moieties. Ligands from this series can act as inhibitors of Tat-induced transcription in a cell-free system. This study validates the drug design strategy of using a ligand to target the RNA receptor in a non-functional conformation.

PubMed: 15095977
DOI: 10.1016/j.jmb.2003.12.028

Experimental method

SOLUTION NMR